US4224342A - Guanidinobenzoic acid compounds and process for preparing the same - Google Patents

Guanidinobenzoic acid compounds and process for preparing the same Download PDF

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Publication number
US4224342A
US4224342A US05/959,276 US95927678A US4224342A US 4224342 A US4224342 A US 4224342A US 95927678 A US95927678 A US 95927678A US 4224342 A US4224342 A US 4224342A
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United States
Prior art keywords
acid
addition salts
guanidinobenzoyloxy
group
guanidinobenzoic
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Expired - Lifetime
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US05/959,276
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English (en)
Inventor
Setsuro Fujii
Tsuyoshi Watanabe
Masashi Shiota
Okumoto Itsuo
Naohiro Kayama
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Ono Pharmaceutical Co Ltd
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Ono Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/18—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to novel guanidinobenzoic acid compounds and processes of producing the guanidinobenzoic acid compounds.
  • trans-4-aminomethylcyclohexanecarboxylic acid as disclosed in S. Okamoto and U. Okamoto, Keio Journal of Medicine, 11, 105 (1962) is known to be an anti-plasmin agent.
  • "Trasylol” as described in B. Kassel et al, J. Biol. Chem., 238, 3274 (1963) and German Patent Application (OLS) No. 1,905,813 is known to be an anti-trypsin agent
  • the compounds disclosed in U.S. Pat. No. 4,021,472 are known to be both an anti-plasmin agent and an anti-trypsin agent.
  • trans-4-aminomethylcyclohexanecarboxylic acid and Trasylol have disadvantages because they exhibit relatively low activities.
  • the compounds described in U.S. Pat. No. 4,021,472 provide the same anti-plasmin or anti-trypsin effect at a lower dosage level than can be achieved with trans-4-aminomethylcyclohexanecarboxylic acid and Trasylol.
  • An object of this invention is, therefore, to provide guanidinobenzoic acid compounds which are useful as pharmaceuticals.
  • Another object of this invention is to provide guanidinobenzoic acid compounds of high potency with respect to anti-plasmin or anti-trypsin pharmacological activities at low dosage levels and to provide a process for preparing such compounds.
  • Another object of the present invention is to provide a pharmaceutical composition having antiplasmin and anti-trypsin activity:
  • a further object of the present invention is to provide a method for inhibiting the activity of plasmin and/or trypsin.
  • this invention in one embodiment provides guanidinobenzoic acid compounds represented by the formula (I) ##STR2## wherein Z represents a methylene group, an ethylene group or a vinylene group, and R represents a hydrogen atom or a lower alkyl group, the acid addition salts of the guanidinobenzoic acid compounds represented by the formula (I).
  • this invention provides a process for preparing the guanidinobenzoic acid compounds represented by formula (I). ##STR3## wherein Z represents a methylene group, an ethylene group or a vinylene group; and R represents a hydrogen atom or a lower alkyl group, and the acid addition salts thereof according to claim 1, comprising reacting a compound represented by the formula (II) ##STR4## wherein X represents a halogen atom or an acid addition salt thereof with a compound represented by the formula (III) ##STR5## wherein Z has the same meaning as described above, and R' represents a hydrogen atom, a lower alkyl group or a protective group for a carboxylic acid group, and removing the protective group for a carboxylic acid group when R' represents a protective group for a carboxylic acid group.
  • lower alkyl as is used throughout the specification and claims means a straight or branched chain alkyl group having 1 to 3 carbon atoms such as a methyl group, an ethyl group, n-propyl and isopropyl groups.
  • novel guanidinobenzoic acid compounds can be prepared according to the following reaction scheme: ##STR6## wherein Z and R are as defined above; X represents a halogen atom and R' represents a hydrogen atom, a lower alkyl group or a protective group for a carboxylic acid group.
  • the compounds of the formula (I) can be prepared by reacting a p-guanidinobenzoyl halide represented by the formula (II) or an acid addition salt thereof with a compound represented by the formula (III) in the presence of an inert solvent and a dehydrohalogenating agent at a temperature ranging from -20° C. to room temperature (about 10°-25° C.) for about 1 to 5 hours and then removing the protective group for a carboxylic acid group where R' represents such a protective group.
  • dehydrohalogenating agents which can be used include tertiary amines such as triethylamine, tributylamine, N,N-dimethylaniline, N-methylpiperidine, pyridine, etc.
  • inert solvents which can be used in this invention include benzene, toluene, diethyl ether, tetrahydrofuran, dioxane, acetone, acetonitrile, pyridine, etc.
  • inert solvents described above can be used individually or as a mixture thereof.
  • pyridine is most preferred since it serves both as a solvent and as a dehydrohalogenating agent.
  • R' in the compounds represented by the formula (II) may be a hydrogen atom or a lower alkyl group, a protective group for a carboxylic acid group. It is, however, preferred to protect the carboxylic acid group.
  • Suitable examples of protective groups for carboxylic acid groups represented by R' which can be used in this invention include conventional protective groups for carboxylic acid groups such as a benzyl group, a t-butyl group, a trialkyl silyl group, e.g., a trimethylsilyl group, a p-methoxybenzyl group, etc., preferably a benzyl group and a t-butyl group with a benzyl group being most preferred.
  • the reaction product produced is in the form of an acid addition salt thereof.
  • the acid addition salt reaction product may be isolated as it is by filtering the crystals precipitated in the reaction mixture or by adding an aqueous solution of sodium bicarbonate to the reaction mixture, thereby crystallizing the product in the form of a carbonate or an inner salt followed by filtration.
  • R' represents a hydrogen atom
  • the compound represented by the formula (I) is obtained as an inner salt
  • R' represents a lower alkyl group or a protective group for a carboxylic acid group the compound is obtained as a carbonate salt.
  • the protective group can be removed in a conventional manner.
  • acid addition salts of the compound represented by the formula (I) can be obtained by removing the protective group for the carboxylic acid group by treating it with a mixed solution of hydrobromic acid and acetic acid when R' represents a benzyl group and with an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, etc. when R' represents a t-butyl group, a p-methoxybenzyl group, etc.
  • the compound represented by the formula (I) can further be converted into pharmaceutically acceptable acid addition salts thereof with ease according to conventional methods, if desired.
  • acids which can be used to produce the pharmaceutically acceptable acid additon salts include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, etc., and organic acids such as maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, etc.
  • Preferred examples of pharmaceutically acceptable acid addition salts of the compound represented by the general formula (I) include methanesulfonates, toluene sulfonates, hydrochlorides, phosphates, etc.
  • the compounds of the formula (II) can be prepared from p-guanidinobenzoic acid in a conventional manner.
  • p-guanidinobenzoic acid is heated with thionyl chloride to form p-guanidinobenzoyl chloride hydrochloride, which can be used per se for further reaction in this invention.
  • thionyl chloride to form p-guanidinobenzoyl chloride hydrochloride, which can be used per se for further reaction in this invention.
  • the compounds represented by the formula (I) and the acid addition salts thereof have potent anti-plasmin and anti-trypsin activities even at very low dosage levels.
  • guanidinobenzoic acid compounds represented by the formula (I) and the acid addition salts thereof according to this invention are highly inhibitory to plasmin and trypsin and, therefore, are useful as pharmaceuticals, i.e., as an anti-trypsin agent for treating acute pancreatitis and the like or as an anti-plasmin agent for treating bleeding disorders and the like.
  • compositions comprising at least one of the compounds represented by the general formula [I] or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers diluents and excipients.
  • the compounds or pharmaceutical compositions comprising the same are administered orally.
  • suitable examples of solid formulations for oral administration include tablets, pills, powders and granules.
  • one or more active ingredients are mixed with at least one inactive diluent such as calcium carbonate, potato starch, alginic acid, lactose, etc.
  • the formulation may contain additives other than the diluents, for example, lubricants such as magnesium stearate, etc.
  • liquid formulations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • Conventionally used liquid diluents are, for example, water or liquid paraffin.
  • This formulation may also contain, in addition to the diluents, auxiliary agents, for example, humectants, suspension aids, sweeteners, flavors, fragrants or antiseptics.
  • Capsules comprising an assimilable substance such as gelatin and which contain one or more active ingredients and a diluent or an excipient can also be used in this invention as a suitable example of formulation for oral administration.
  • the amount of the active ingredient in the formulation can be varied and a suitable amount determined depending on the therapeutic purpose. Dosage is determined based on the therapeutic effects desired, the number of times administered and the period of treating.
  • the dosage for an adult is about 100 mg to about 1 g per patient per day for treating acute pancreatitis and hemorrhagic diseases by oral administration.
  • Acute toxicity of 4-(4-guanidinobenzoyloxy)phenylacetic acid mesylate is 4500 mg/kg in mice and 4400 mg/kg in rats.
  • guanidinobenzoic acid compounds represented by formula (I) of this invention include p-(guanidinobenzoyloxy)phenylacetic acid, 3-[p-(p-guanidinobenzoyloxy)penyl]propionic acid, p-(p-guanidinobenzoyloxy)cinnamic acid, methyl p-(p-guanidinobenzoyloxy)phenyl acetate, ethyl p-(p-guanidinobenzoyloxy)phenyl acetate, n-propyl p-(p-guanidinobenzoyloxy)phenyl acetate, isopropyl p-(p-guanidinobenzoyloxy)phenyl acetate, methyl p-(p-guanidinobenzoyloxy)phenyl propionate, ethyl p-(p-guanidinobenzoyloxy)phenylpropionat
  • the crystals thus obtained were added to 250 ml of pyridine, having 23 g of benzyl p-hydroxyphenylacetate dissolved therein at -20° C. and the mixture was stirred at 0° C. for 5 hours.
  • the reaction mixture was filtered and the filtrate was concentrated to about half the original volume followed by adding diethyl ether thereto.
  • the oily product obtained was removed by decantation and water was added thereto.
  • the dried crystals were dissolved in a mixed solvent of water-methanol (v/V ratio: 1:1) followed by adding saturated aqueous solution of sodium bicarbonate to precipitate crystals of p-(p-guanidinobenzoyloxy)phenylacetic acid having a melting point of 242° to 246° C.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US05/959,276 1977-11-09 1978-11-09 Guanidinobenzoic acid compounds and process for preparing the same Expired - Lifetime US4224342A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP52-133379 1977-11-09
JP13337977A JPS5470241A (en) 1977-11-09 1977-11-09 Guanidinobenzoic acid derivative and its preparation

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US (1) US4224342A (en, 2012)
JP (1) JPS5470241A (en, 2012)
DE (1) DE2846251A1 (en, 2012)
FR (1) FR2408584A1 (en, 2012)
GB (1) GB2007653B (en, 2012)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4423069A (en) * 1982-01-20 1983-12-27 University Of Illinois Foundation Contraceptive method
US4490388A (en) * 1981-02-27 1984-12-25 Torii & Co., Ltd. Amidine compound and anticomplement agent comprising same
US4681895A (en) * 1985-03-08 1987-07-21 Kanebo, Ltd. Novel guanidinomethylcyclohexanecarboxylic acid compounds and anti-ulcer drug containing the same
US4801603A (en) * 1985-12-27 1989-01-31 Eisai Co., Ltd. Guanidinobenzoic ester derivative
US6066673A (en) * 1998-03-12 2000-05-23 The Procter & Gamble Company Enzyme inhibitors
EP0893437A4 (en) * 1996-04-10 2000-12-27 Ono Pharmaceutical Co GUANIDINO TRYPTASE INHIBITOR
US6489308B1 (en) 1999-03-05 2002-12-03 Trustees Of University Of Technology Corporation Inhibitors of serine protease activity, methods and compositions for treatment of nitric-oxide-induced clinical conditions
US20040220239A1 (en) * 2003-05-02 2004-11-04 Leland Shapiro Inhibitors of serine protease activity methods and compositions for treatment of nitric oxide-induced clinical conditions
US20050106151A1 (en) * 2003-08-26 2005-05-19 Leland Shapiro Inhibitors of serine protease activity and their use in methods and compositions for treatment of bacterial infections
US20060040867A1 (en) * 1999-03-05 2006-02-23 Leland Shapiro Inhibitors of serine protease activity and their use in methods and compositions for treatment of bacterial infections
US20080051330A1 (en) * 1999-03-05 2008-02-28 Leland Shapiro Inhibitors of serine protease activity, methods and compositions for treatment of herpes viruses
US9938353B2 (en) 2011-06-24 2018-04-10 The Regents Of The University Of Colorado, A Body Corporate Compositions, methods and uses for alpha-1 antitrypsin fusion molecules
US10478508B2 (en) 2012-01-10 2019-11-19 The Regents Of The University Of Colorado, A Body Corporate Compositions, methods and uses for alpha-1 antitrypsin fusion molecules

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2044760B (en) 1979-03-01 1983-03-23 Ono Pharmaceutical Co Guanidinobenzoic acid derivatives
US5247084A (en) * 1985-11-12 1993-09-21 Ono Pharmaceutical Co., Ltd. Derivatives of p-guanidinobenzoic acid
US4843094A (en) * 1985-11-12 1989-06-27 Ono Pharmaceutical Co., Ltd. Derivatives of p-guantidinobenzoic acid and pharmaceutical agents containing them as active ingredient
EP0222608B1 (en) * 1985-11-12 1991-09-11 Ono Pharmaceutical Co., Ltd. Derivatives of p-guanidinobenzoic acid and pharmaceutical agents containing them as active ingredient

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4911842A (en, 2012) * 1972-05-12 1974-02-01
JPS5116631A (ja) * 1974-07-31 1976-02-10 Ono Pharmaceutical Co Guanijinoansokukosanjudotaino seizohoho
US4021472A (en) * 1974-11-01 1977-05-03 Ono Pharmaceutical Co., Ltd. Guanidinobenzoic acid derivatives

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1905813A1 (de) * 1968-07-04 1970-03-05 Akad Wissenschaften Ddr 3- oder 4-Guanidobenzoesaeurebenzyl- oder -phenylestern und deren Verwendung als Inhibitoren

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4911842A (en, 2012) * 1972-05-12 1974-02-01
JPS5116631A (ja) * 1974-07-31 1976-02-10 Ono Pharmaceutical Co Guanijinoansokukosanjudotaino seizohoho
US4021472A (en) * 1974-11-01 1977-05-03 Ono Pharmaceutical Co., Ltd. Guanidinobenzoic acid derivatives

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4490388A (en) * 1981-02-27 1984-12-25 Torii & Co., Ltd. Amidine compound and anticomplement agent comprising same
US4423069A (en) * 1982-01-20 1983-12-27 University Of Illinois Foundation Contraceptive method
US4681895A (en) * 1985-03-08 1987-07-21 Kanebo, Ltd. Novel guanidinomethylcyclohexanecarboxylic acid compounds and anti-ulcer drug containing the same
US4801603A (en) * 1985-12-27 1989-01-31 Eisai Co., Ltd. Guanidinobenzoic ester derivative
EP0893437A4 (en) * 1996-04-10 2000-12-27 Ono Pharmaceutical Co GUANIDINO TRYPTASE INHIBITOR
US6388122B1 (en) 1996-04-10 2002-05-14 Ono Pharmaceutical Co., Ltd. Tryptase inhibitor and novel guanidino derivatives
US6066673A (en) * 1998-03-12 2000-05-23 The Procter & Gamble Company Enzyme inhibitors
US20080051330A1 (en) * 1999-03-05 2008-02-28 Leland Shapiro Inhibitors of serine protease activity, methods and compositions for treatment of herpes viruses
US7807781B2 (en) 1999-03-05 2010-10-05 The Regents Of The University Of Colorado Inhibitors of serine protease activity and their use in methods and compositions for treatment of viral infections
US20060040867A1 (en) * 1999-03-05 2006-02-23 Leland Shapiro Inhibitors of serine protease activity and their use in methods and compositions for treatment of bacterial infections
US6489308B1 (en) 1999-03-05 2002-12-03 Trustees Of University Of Technology Corporation Inhibitors of serine protease activity, methods and compositions for treatment of nitric-oxide-induced clinical conditions
US20040220113A1 (en) * 2003-05-02 2004-11-04 Leland Shapiro Inhibitors of serine protease activity methods and compositions for treatment of nitric oxide-induced clinical conditions
US20040220242A1 (en) * 2003-05-02 2004-11-04 Leland Shapiro Inhibitors of serine protease activity, methods and compositions for treatment of nitric oxide induced clinical conditions
US20040220239A1 (en) * 2003-05-02 2004-11-04 Leland Shapiro Inhibitors of serine protease activity methods and compositions for treatment of nitric oxide-induced clinical conditions
US20070224671A1 (en) * 2003-05-02 2007-09-27 Leland Shapiro Inhibitors of serine protease activity methods and compositions for treatment of nitric oxide-induced clinical conditions
US20110021416A1 (en) * 2003-08-26 2011-01-27 Leland Shapiro Compositions, methods and uses for treating bacterial infections
US20100137192A1 (en) * 2003-08-26 2010-06-03 Leland Shapiro Compositions and methods for treating or ameliorating mycobacterial infections
US7850970B2 (en) 2003-08-26 2010-12-14 The Regents Of The University Of Colorado Inhibitors of serine protease activity and their use in methods and compositions for treatment of bacterial infections
US20050106151A1 (en) * 2003-08-26 2005-05-19 Leland Shapiro Inhibitors of serine protease activity and their use in methods and compositions for treatment of bacterial infections
EP2520654A1 (en) 2003-08-26 2012-11-07 The Regents of the University of Colorado Inhibitors of serine protease activity and their use in methods and compositions for treatment of bacterial infections
US8633305B2 (en) 2003-08-26 2014-01-21 Leland Shapiro Compositions of, and methods for, alpha-1 anti trypsin Fc fusion molecules
US9499606B2 (en) 2003-08-26 2016-11-22 The Regents Of The University Of Colorado, A Body Corporate Compositions of, and methods for, alpha-1 anti trypsin Fc fusion molecules
US9695229B2 (en) 2003-08-26 2017-07-04 The Regents Of The University Of Colorado, A Body Corporate Compositions of, and methods for, alpha-1 antitrypsin Fc fusion molecules
EP3192872A1 (en) 2003-08-26 2017-07-19 The Regents of the University of Colorado, a body corporate Inhibitors of serine protease activity and their use in methods and compositions for treatment of bacterial infections
US10913790B2 (en) 2003-08-26 2021-02-09 The Regents Of The University Of Colorado, A Body Corporate Compositions of, and methods for, alpha-1 anti trypsin Fc fusion molecules
US9938353B2 (en) 2011-06-24 2018-04-10 The Regents Of The University Of Colorado, A Body Corporate Compositions, methods and uses for alpha-1 antitrypsin fusion molecules
US12030958B2 (en) 2011-06-24 2024-07-09 The Regents Of The University Of Colorado Compositions and methods of use of alpha-1 antitrypsin fusion polypeptides
US10478508B2 (en) 2012-01-10 2019-11-19 The Regents Of The University Of Colorado, A Body Corporate Compositions, methods and uses for alpha-1 antitrypsin fusion molecules

Also Published As

Publication number Publication date
FR2408584B1 (en, 2012) 1983-12-09
FR2408584A1 (fr) 1979-06-08
GB2007653A (en) 1979-05-23
JPS5470241A (en) 1979-06-05
GB2007653B (en) 1982-04-07
DE2846251A1 (de) 1979-05-10
JPS5735870B2 (en, 2012) 1982-07-31
DE2846251C2 (en, 2012) 1988-08-04

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